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1. Introduction

2. Overview of direct Xa

inhibitors in treatment of VTE

3. Which patients (not) to treat

with Xa inhibitors?

4. Which Xa inhibitor to use?

5. Which dose of Xa inhibitor to

use?

6. Conclusion

7. Expert opinion

Review

Pharmacotherapy with oral Xainhibitors for venousthromboembolismThomas Vanassche, Christophe Vandenbriele, Kathelijne Peerlinck &Peter Verhamme

KU Leuven-- University of Leuven, Vascular Medicine and Haemostasis, Department of

Cardiovascular Sciences, Leuven, Belgium

Introduction: Venous thromboembolism (VTE) causes substantial morbidity

and mortality worldwide. The traditional treatment of VTE, with an initial

therapy with (low molecular weight) heparin or fondaparinux and a contin-

ued treatment with vitamin K antagonists, is effective but has limitations.

Areas covered:The current review summarizes the results of the Phase III trials

with the new oral direct factor Xa inhibitors rivaroxaban, apixaban and edox-

aban and provides a meta-analysis of these trials in the subgroups of elderly

patients (> 75 years) and patients with impaired renal function.Expert opinion: The practical use of direct Xa inhibitors in the treatment of

VTE in general and in specific subgroups is discussed. For elderly patients,

patients with extremes of body weight, cancer patients or patients with mod-

erate renal impairment, pooled data suggest that the direct oral Xa inhibitors

are a reasonable alternative to standard therapy. For other indications, such

as treatment of VTE in children, during pregnancy or in the context of

heparin-induced thrombocytopenia, further data from clinical trials

are needed.

Keywords:apixaban, deep vein thrombosis, edoxaban, factor X, oral anticoagulants, pulmonary

embolism, rivaroxaban, venous thromboembolism

Expert Opin. Pharmacother. [Early Online]

1. Introduction

1.1 Burden of venous thromboembolism

The best-known clinical presentations of venous thromboembolism (VTE) are deepvein thrombosis (DVT) of the lower limb and pulmonary embolism (PE). Long-term complications of VTE include recurrent disease, post-thrombotic syndromeand chronic thromboembolic pulmonary hypertension [1]. Other manifestations ofthe disease spectrum include cerebral and splanchnic vein thrombosis, upper limbDVT, distal DVT and superficial thrombophlebitis [2].

VTE is a cause of substantial morbidity and mortality worldwide. The total inci-dence of VTE is estimated at 0.7 --1.13 per 1000 persons per year, and increaseswith age [3]. PE is the most preventable cause of death in hospitalized patients,and the prevention of VTE is among the top priorities when it comes to improvingthe quality of healthcare [4]. In 2004, it was estimated that > 1 million venousthromboembolic events occur each year in France, Germany, Italy, Spain, Swedenand the UK combined, and ~ 12% of all deaths occurring in these six countrieswere attributable to VTE [5].

1.2 Physiology and pathophysiology of Xa

Factor X, also known as Stuart factor, is a central enzyme in the coagulation cascade.Just as for factors II, VII and IX, the synthesis of factor X in the liver requires vitamin

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K asa cofactor for g-glutamyl carboxylase, an enzyme that addsa negatively charged carboxyl group required for the interac-tion with calcium. Following tissue or vessel wall damage,exposed tissue-factor binds factor VII. Together, tissue-factorand factor VIIa form a complex that activates factor IX and

X. After activation, Xa associates with factor V to form the pro-thrombinase complex, activating prothrombin to thrombin.Thrombin activation triggers an amplification loop throughthe activation of factor V, XI and VIII. Factor VIIIa togetherwith IXa forms the tenase complex, activating more factor X,

leading to more thrombin generation (Figure 1A).

1.3 Anticoagulants targeting Xa

The challenge in the treatment of VTE is to provide a therapythat is effective, safe and convenient. Due to the central role offactor X in both the initiation and the amplification of throm-bin generation, it is an important target for anticoagulantdrugs. Three different classes of anticoagulants act at least inpart by interfering with Xa activity (Table 1, Figure 1B --D).

1.4 Establishing efficacy

The first use of anticoagulants to treat VTE was in the 1930sand 1940s [6]. Unfractionated heparin (UFH) drasticallyreduced mortality in patients with VTE, but was unpracticalfor continued treatment due to its intravenous administrationand its very short half-life. In contrast, vitamin K antagonists(VKA) could be administered orally, but the onset of actionwas too slow to provide adequate efficacy in the first days oftreatment. Hence, the combination of an initial treatmentwith short-acting heparins, overlapping and followed by acontinued treatment with VKA became the standard treat-ment for VTE for the next five to six decades.

1.5 Improving safety

Due to the highly unpredictable anticoagulant effect of bothUFH and VKAs, monitoring techniques were developed andstandardized, that is, the activated partial thromboplastintime for UFH and the prothrombin time expressed as interna-tional normalized ratio for VKAs, which improved the efficacyand safety of these drugs by allowing to titrate their activity.

1.6 Improving convenience

Next was the search for drugs with more predictable pharmaco-kinetic profiles. The use of heparin molecules with a limitedchain length, that is, low molecular weight heparins (LMWHs),removed the need for routine laboratory monitoring because oftheir more predictable anticoagulant effect. LMWHs also nar-row the spectrum of antithrombin-mediated inactivation tomainly factor Xa, though the exact spectrum of LMWHs stilldepends on the mixture of heparin molecules with variable chainlengths. In contrast, the small synthetic pentasaccharide fonda-

parinux, which mimics the antithrombin binding site of hepa-rins, only catalyzes the inactivation of factor Xa (Figure 1). Theuse of a fixed dose of LMWH or fondaparinux greatly improvedconvenience of VTE therapy and promoted outpatient therapy.However, their use for continued treatment remained limiteddue to the need for parenteral administration.

The development of direct oral Xa inhibitors aimed atcombining the predictable anticoagulant effect with oraladministration. Three direct Xa inhibitors (rivaroxaban, apix-aban, edoxaban) have been evaluated in large Phase III pro-grams for various indications, whereas other Xa inhibitorsare still in development (betrixaban).

In this overview, we aim to summarize the results of the

Phase III trials with rivaroxaban, apixaban and edoxaban forthe treatment of VTE, and translate the trial results into prac-tical clinical recommendations. Dabigatran, an oral directthrombin inhibitor, has also been recently approved for thetreatment and secondary prevention of VTE, but is discussedelsewhere [7].

2. Overview of direct Xa inhibitors intreatment of VTE

2.1 Search strategy and meta-analysis

We limited this review to Xa inhibitors (summarized

in Table 2) that are either approved for the treatment ofVTE or under consideration for such approval by the Euro-pean Medicine Agency. Phase III randomized controlled trialscomparing the Xa inhibitors with VKA therapy for the initialtreatment of VTE were included. From these trials, availableanalyses for different subgroups (such as age, body weight,cancer, renal function, etc.) were obtained from the originalpublications, from their online supplements and abstract pre-sentations at major conferences.

We performed a meta-analysis for the relative efficacy aswell as safety of the different Xa inhibitors versus VKA in

Article highlights.

. Rivaroxaban, apixaban and edoxaban were as effectiveas low molecular weight heparins followed by vitamin Kantagonists in the Phase III trials. Real-life data fromregistries are yet to become available.

. All Xa inhibitors were associated with lower rates ofbleeding, especially fatal bleeds and intracranial bleeds.

. Direct Xa inhibitors are a valid treatment of venousthromboembolism (VTE) for the majority of patients, butsome important patient groups were not adequatelyrepresented in Phase III trials.

. For elderly patients, patients with extremes of bodyweight, cancer patients or patients with moderate renalimpairment, pooled data strongly suggest that the directoral Xa inhibitors are a reasonable alternative tostandard therapy.

. Further trials are needed for these subgroups and forthe use of oral Xa inhibitors in treatment of VTE inchildren, heparin-induced thrombocytopenia orduring pregnancy.

This box summarizes key points contained in the article.

T. Vanassche et al.

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patients over 75 years and in patients with a reduced renalclearance (cutoff of a creatinine clearance [CrCl]of50 ml/min; Cockroft-Gault formula). Risk ratios (RRs)and corresponding 95% CIs were calculated for the individualtrials and pooled according to the Mantel-Haenszel method,using a random effect model (Review Manager 5.2).

2.2 Similarities in trials

The Phase III programs of rivaroxaban [8,9], apixaban [10,11]and edoxaban [12] are summarized in Table 3. They werevery similar in terms of inclusion and exclusion criteria,

leading to very comparable study populations. All three pro-grams included patients with acute symptomatic PE and/orDVT, with the majority of cases presenting with unprovokedVTE. Although the total number of patients included in thetrials is very large, it is important to note that certain patientpopulations were not included, or constituted only a smallpart of the study populations (Table 3).

2.3 Differences between trials

Some important differences in terms of trial design areworth highlighting.

Surfaces

fXlla

fXla

flXa

fVllla

fVlla

Tissue injury

Tissue factor

fVa

FibrinFibrinogen

Central role of Xa in coagulation cascace Vitamin K antagonists:reduction of functional factor II, VII, IX, and X

fXa

flla

Surfaces

fXlla

fXla

flXa fVlla

Direct Xa inhibitors

Direct Xa inhibitors:direct inhibition of factor Xa

Heparins:indirect inhibition: potentiation of antithrombin activity

Tissue injury

Tissue factor

FibrinFibrinogen

fXa

flla

Surfaces

Hepatic synthesis

VKA

fXlla

fXla

flXa fVlla

Tissue injuryFunctionalmaturation

Tissue factor

FibrinFibrinogen

fXa

flla

Surfaces

fXlla

fXla

flXa fVlla

Tissue injury

Tissue factor

FibrinFibrinogen

Antithrombin

Syntheticpentasaccharides

Antithrombin

LMWHUFH

Antithrombin

fXa

flla

A. B.

C. D.

Figure 1. A.The central role of factor Xa in the coagulation cascade. B.VKA inhibit VK epoxy reductase. By preventing the VK-

dependent g-carboxylation, VKA lead to the synthesis of inactive forms of the factors II, VII, IX and X. C. Heparin and itsderivatives are indirect Xa inhibitors that act by increasing the activity of antithrombin, a physiological inhibitor of factors X,

II, XI and XII. UFH consists of a mixture of heparin molecules of different lengths. Binding of the AGA*IA-pentasaccharide

sequence to antithrombin strongly potentiates the inhibition of factor Xa by antithrombin. In a similar way, heparin-bound

antithrombin can also inhibit factor XIa and thrombin, but this requires the binding of additional domains in the heparin

molecules to the clotting factors. LMWHs consist of a fraction of heparin molecules with shorter chain lengths compared with

UFH and mainly exert their anticoagulant effect through factor Xa inhibition. Due to a smaller fraction of molecules with a

chain length sufficiently long to form the XIa--antithrombin and IIa--antithrombin complex, LMWH inhibits thrombin and

factor XIa to a lesser extent compared with UFH. Fondaparinux and idraparinux are synthetic pentasaccharides that bind to

antithrombin and potentiates its inhibition of factor Xa. Due to the absence of long heparin chains, fondaparinux and

idraparinux selectively inhibit factor Xa without affecting other clotting factors. D. Direct Xa inhibitors directly bind to the

active site of Xa, blocking the activity of Xa.LMWH: Low molecular weight heparin; UFH: Unfractionated heparin; VKA: Vitamin K antagonist.

Pharmacotherapy with oral Xa inhibitors for venous thromboembolism

Expert Opin. Pharmacother. (2014) 16 (5) 3


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2.3.1 BlindingThe rivaroxaban trials (EINSTEIN-DVT and EINSTEIN-PE) were open-label trials with blinded outcome adjudication,whereas the trials with edoxaban (HOKUSAI) and apixaban(AMPLIFY) were double blind. The pros and cons of open-label versus double-blind studies when a VKA is the compar-ator have been discussed extensively [13,14].

2.3.2 Initial treatment

A major difference in the Phase III clinical trials of apixaban,edoxaban and rivaroxaban is their initial treatment of acuteand symptomatic VTE. Failure to rapidly reach therapeutic

levels of anticoagulation is associated with an increased earlyrecurrence [15]. Furthermore, previous experience with thedirect thrombin inhibitor ximelagatran and the indirectlong-acting Xa inhibitor idraparinux suggested that a higherintensity of anticoagulation is required in the initial treatmentphase[16,17]. This need for rapid and effective initial treatmentwas approached differently in the three Phase III programs. Inthe HOKUSAI study, patients received initial therapy with(low molecular weight) heparins for at least 5 days, followedby standard dose edoxaban [12]. In contrast, rivaroxaban andapixaban were started without heparin lead-in, but at a higher

initial dose (15 mg twice daily [b.i.d.] of rivaroxaban for3 weeks, or 10 mg of apixaban b.i.d. for 1 week) [8-10].

2.3.3 Dose adjustment

The HOKUSAI trial used a prespecified dose reduction of30 mg instead of 60 mg once daily (q.d.) in patients withmoderate renal insufficiency, low body weight or concomitantintake of P-glycoprotein inhibitors that increase drug absorp-tion. In contrast, apixaban and rivaroxaban were used in afixed dose of 5 mg b.i.d. or 20 mg q.d., respectively, for thecontinued treatment. Only apixaban has evaluated a reduceddose (2.5 mg b.i.d.) for the long-term secondary prophylaxisor extended treatment in the AMPLIFY-EXT study [11].

2.3.4 Treatment duration

Treatment duration was prespecified at randomization(6 months for apixaban in the AMPLIFY study, 3, 6 or12 months in the EINSTEIN studies) or was up to 12 monthsin HOKUSAI, with the need to evaluate risks and benefits ofcontinuing anticoagulation after 3 and 6 months of treat-ment, reflecting clinical practice.

Table 1. Overview of anticoagulants targeting factor X.

Class Vitamin K

antagonists

Heparins and derivatives Direct oral Xa

inhibitors

Mechanism Lower levels of activefactor

Indirect inhibition: increased rate of antithrombin-mediatedinhibition

Directinhibition: binding to

Xa active siteDrugs UFH LMWH Synthetic pentasaccharides Rivaroxaban, apixaban,

edoxabanFondaparinux Idra(biota)parinux

Spectrum of inhibition II, VII, IX, X II, X, XI, XII X, (II) X X XMonitoring activity PT aPTT Anti-Xa Anti-Xa Anti-Xa Anti-Xa (PT)PK profile Unpredictable Unpredictable Predictable Predictable Predictable PredictableT1/2 Long Very short Short Short Long ShortAdministration p.o. i.v. (s.c.) s.c. s.c. s.c. p.o.

aPTT: Activated partial thromboplastin time; LMWH: Low molecular weight heparin; PT: Prothrombin time.

Table 2. Key pharmacokinetic of the direct Xa inhibitors.

Rivaroxaban Apixaban Edoxaban

Prodrug No No No% renal clearance 35% 30% 50%Half-life 5-- 9 h (young)

11 -- 13 h (elderly)12 h 12 h

Half-life if eGFR < 30 ml/min 10 h No data available 17 hTime to peak plasma level 2-- 4 h 1 -- 4 h 1-- 2 hCYP3A4 substrate Yes Yes MinimalInteraction with food intake Increased absorption, recommended intake

with foodNo No

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Table3.

ComparisonofdesignandpatientpopulationsinPhase

IIItrialsofdirectXainhibitorsfort

hetreatmentofacuteVTE.

Rivaroxaban

Apixaban

Edoxaban

Trial

EINSTEINDVT

EINSTEINPE

AMPLIFY

HOKUSA

I-VTE

Design

Inclusion

SymptomaticVTE(p

roximalDVT

and/orPE)

SymptomaticV

TE(proximalDVT

and/orPE)

Symptom

aticVTE(proximal

DVTand

/orPE)

Studydesign

Open-label

Double-blind,d

ouble-dummy

Double-blind,double-dummy

Initialtreatment

Rivaroxaban15mg

b.i.d.for

3weeksversusLMW

Huntil

INR>2

Apixaban10m

gb.i.d.for1week

versusLMWHuntilINR>2,atleast

5days

LMWHu

ntil(sham)INR>2,

atleast5days

Continuedtreatment

Rivaroxaban20mg

odversus

INR-adjustedVKAtherapy

Apixaban5mg

b.i.d.versus

INR-adjustedw

arfarintherapy

Edoxaba

n60mgodversus

INR-adjustedwarfarin

therapy

Doseadjustment

None

None

30mgo

dinpatientswith

lowbodyweight,reduced

renalcle

aranceor

concomitantintakeofP-gp

inhibitors

Treatmentduration

3,6or12months

6months

Upto12

months

Patientpopulation

N

Rivaroxaban

LMWH/VKA

Apixaban

LMWH/Warfarin

Edoxaban

Warfarin

DVTalone

1731

1718

1698

1736

2468

2453

PE

2419

2413

900

886

1650

1669

Total

4151

4131

2598

2622

4118

4122

Characteristics

Meanage(years)

57.0

56.9

55.8

75years(n,%)

1283(15.5%)

749(14.3%)

1104(13.4%)

Lowbodyweight

108(1.3%)(

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